Our understanding of how cancers begin, survive and progress is rapidly expanding through advances in cancer genomics and modern cancer biology. Although these insights suggest many new strategies for therapeutic intervention, they often require modulating targets against which the research community has had little experience or success developing small-molecule probes and drugs. Through the NCI Molecular Target Discovery and Development Center Network Pilot Program, we aim to overcome this challenge and to accelerate the discovery of novel therapeutics in cancer. The Broad-MTDDC will provide over 10 years of experience in both innovation and execution in small- molecule probe and drug development to the MTDDC Network to advance insights from the cancer biology community. We aim to innovate in fundamental chemistry so as to enable the discovery of small-molecule probes against even 'undruggable'cancer targets such as those emerging from genomic studies;to engage the cancer biology community and to bring small-molecule science to the root causes of cancer;and to solve the target I.D. problem, including by determining comprehensively the proteins to which small-molecule modulators of cancer pathways bind in or on cells. Furthermore, we will provide the cancer biology community with the robust infrastructure and expertise required to execute probe- and drug-development projects that aim to transform cancer therapeutics. Impact on human health. The Molecular Target Discovery and Development Center at the Broad Institute will discover small molecules that target the root causes and dependencies of cancer. These leads will serve as valuable starting points for new drug development programs. By providing early lead optimization and data from clinically relevant animal models, we aim to advance cancer drug discovery development. Furthermore, we will make all data associated with small-molecule probe development publicly available, enabling further discovery from the community and broader communication of our approaches to drug discovery. PUBLIC HEALTH RELEVANCE: The Molecular Target Discovery and Development Center at the Broad Institute will develop and execute small-molecule screens from the cancer biology community aimed at targeting the root causes and dependencies of cancer. We will focus on innovation in chemistry, screening, and preclinical research in order to access targets viewed as 'undruggable'using current tools and approaches. These projects will yield small- molecule probes that both enable pre-clinical validation of therapeutic strategies using animal models and serve as outstanding starting points for drug development.